Growth and neurodevelopment in low birth weight versus normal birth weight infants from birth to 24 months, born in an obstetric emergency hospital in Haiti, a prospective cohort study

Low birthweight (LBW) in neonates is defined as a birth weight of less than 2500 g by the World Health Organization [1]. LBW classification is determined at birth and based on the absolute weight of the baby at birth regardless of gestational age. It is multifactorial in nature and can be caused by preterm delivery or restricted foetal (intra-uterine) growth [2, 3]. The latter can also result in the babies being small for gestational age (SGA), which is most commonly defined as a baby with a weight below the 10th percentile for the gestational age [4]. Numerous studies have identified the factors, in addition to prematurity, that contribute to LBW including deprived socio-economic conditions of the mother (poor nutrition, poor access to care, high prevalence of infections and high prevalence of pregnancy complications), and maternal health during pregnancy (nutrition, diet, use of alcohol/drugs/tobacco, infections and presence of hypertension and diabetes) [2].

The survival rates of LBW infants have improved with improved clinical management. However, this group of infants remains at risk of higher mortality and morbidity during the neonatal period (i.e. within 28 days after birth) and thereafter. LBW is known to be associated with subsequent health issues such as poor anthropometric growth in childhood and higher incidence of non-communicable disease in adulthood such as hypertension, stroke, diabetes, and hypercholesterolemia and with long term neurological problems (physical and learning disabilities) [5‐7]. Several studies carried out in high resource settings have identified that surviving preterm and/or LBW infants (compared to NBW infants) followed up after birth (up to a maximum of 11 years) suffered from cerebral palsy, visual disability (blindness), deafness, problems with walking and poor performance on neurodevelopmental assessments [6, 8‐13].

Haiti is the poorest country in the Americas with recent estimates that 59% of Haitians live under the national poverty line [14]. The prevalence of pre-eclampsia in pregnant women (an important cause of prematurity and delivery of small-for-gestational age infants) in Haiti is high, estimated at 18% in 2005 [15, 16]. The ‘Centre de Référence des Urgences Obstetricales’ (CRUO) was established by Médecins Sans Frontières (MSF) in Port au Prince (the capital) in 2010 to manage the high number of complicated deliveries (especially women suffering from pre-eclampsia). A neonatal ward was also established to care for the high burden of LBW and/or premature neonates born to women with complicated pregnancies. Between January 2013 and June 2018, out of the 31,509 maternal admissions in CRUO, 34.9% were women that had (pre-) eclampsia and of the 24,983 deliveries documented in the hospital, 11,008 (44.1%) were LBW babies (MSF unpublished data).

Public health structures (or organisations) able to manage long term care for infants with morbidities resulting from their prematurity or LBW are extremely limited in Haiti. Assessing neurodevelopmental outcomes in these infants may help clinical decisions to be made thoughtfully for neonatal care and ongoing support in humanitarian settings. We undertook a prospective cohort study to describe and compare the anthropometric growth (in terms of weight and length) and neurodevelopment between LBW and normal birthweight (NBW) infants born at CRUO. We hypothesized that growth and neurodevelopment outcomes would be poorer in the LBW group compared to the NBW group within 24 months after their birth.

We have described the first ever cohort of Haitian NBW and LBW babies followed for up to 24 months of age in an urban low resource setting. We have shown that LBW babies in this context had a higher risk of death in the neonatal period compared to NBW babies due to their exposure to an ongoing outbreak of K. pneumonia as well as having other morbidities associated with prematurity. LBW babies gained weight more rapidly compared to their NBW counterparts in the first three months of life, which can be seen as catch-up growth. Such catch up growth has been shown to be associated with improved renal and general health [26, 27]. Even so, we estimated that at 24 months of life, LBW babies had lower weight measurements compared to NBW babies. The rapid growth in length in the first three months of life was seen in both NBW and LBW babies, with LBW estimated to be almost caught up to the NBW group at 24 months of age.

The rapid weight gain in the first three months of life in the LBW baby group (15.8 g/kg/day) was close to that observed in extremely LBW babies included in a recent study in South Africa [28]. It is also remarkably close to the standard growth per kilogram per day of 15 g/kg/day [29]. The comparatively slower growth per day (11.4 g/kg/day) in the NBW group (most of whom were never admitted to the hospital post birth), could be partially explained by the fact that LBW babies were followed more closely (during hospitalisation) in terms of breastfeeding and nutrition practices of their mothers as a part of the KMC component in the hospital. Even so, the important stunting (WHZ scores lower than − 2) observed in both the LBW and NBW group at birth and up to 12 months of age suggests that nutrition and feeding practices are a challenge in Haiti. This was described previously in Haiti and was thought to be due to a breakdown in the parent-child relationship [30]. Stunting has been repeatedly shown to be a risk factor for delayed neurodevelopment. A meta-analysis in infants across 15 low and middle income (LMIC) countries showed the negative association between stunting and development [31]. A recent study in Rwanda also showed that LBW and NBW babies that were stunted were significantly more likely to experience developmental delay compared to non-stunted NBW babies [32].

The Bayley III scale is a protocolized manner of measuring the neurodevelopment of our study cohort. Across all categories (motor, cognitive and communication), NBW babies were estimated to have higher raw scores compared to LBW babies for the duration of the study period. An unexpected finding was that NBW and LBW babies were estimated to perform similarly at all age groups for fine motor skills, but larger differences existed for the estimated gross motor skills in the same age groups. We are unable to explain this observation but hypothesize that it might have to do with the sequence in which Haitian children acquire gross and motor skills (which might differ in other countries). Larger differences between NBW and LBW were estimated for cognitive and communication skills, with the largest proportional differences estimates for expressive communication skills (and NBW babies performing better in these categories). This suggests that the cognitive development and communication of LBW babies in Haitian society are delayed. This is not unexpected and has been well described in other studies [33].

One unexpected finding from this study was that male babies had consistently higher estimates for weight, length, cognitive skills and communication skills in both the NBW and LBW groups. In contrast, most studies report that female infants consistently outperform their male counterparts in both development and mortality. Two recent studies (one in Slovenia and Croatia and one in South Africa), showed that females consistently outperformed male infants in Bayley III cognitive and communication skills [34, 35]. Also, globally it has been shown that female preterm babies have better overall mortality outcomes than male babies [36]. The hypothesis for this being that immunological responses (both innate and adaptive) are different between male and female babies and that these determine how they respond to disease and their overall clinical outcomes [37]. We were unable to find much evidence in line with this specific finding. Studies from South Asia in the 1970s and 1980s showed that female infant mortality exceeded that of males in the age group in the second half of their first year of life [38, 39]. These findings were explained by a behavioral preference for nutrition and healthcare of male babies, possibly influenced by having to make selective decisions of the allocation of scarce resources (39,40). In Haiti, our study team reported anecdotally, that parental interactions with male babies are preferred over female babies, both in terms of attention by the mother and surrounding persons. This remains speculative, but this would also suggest that in the Haiti environment, in terms of nutrition and cognitive and communication stimulus, male babies would advance more compared to females.

This study faced numerous limitations. The unexpected high mortality in the LBW baby group due to the hospital acquired outbreak in the neonatal care unit, probably meant that a large proportion of the most vulnerable LBW babies did not survive for the remainder of the study period. The results of this study therefore cannot be extrapolated to all LBW babies, as the study group likely represents the ‘stronger’ babies that were enrolled in the cohort. Also, partially due to this high mortality, we did not achieve the original calculated study sample size. Considering the narrow confidence intervals obtained from our estimates, we do not think this impacted on the power of our study. We were unable to reliably adjust for prematurity in the models for physiological growth and neurodevelopment as gestational age measurements in Haiti were done through a variety of methods and were not standardized. This limitation is well acknowledged in similar studies in low resource settings as distinguishing between LBW, SGA and prematurity (or a combination of these) where unreliable gestational age measurements is difficult (41). There are no validated Bayley III scales for Haiti, thus we were unable to compare the scores of our study cohort to a standardized population and the comparison could only be done between the NBW and LBW groups. The sample size requirements to validate the Bayley III scales for the Haitian population were too large to be feasible to explore in the current study. We also we unable to calculate reliably the intra and inter-reliability between study teams for their neurodevelopmental assessments. Even though we minimized differences by conducting quality control checks and discussing discrepancies, we could not account for these in our final analysis. Finally, for the Bayley III scales regression models, we only had three or four follow up visit data from the study cohort. This limited the ability to introduce more knots into the regression models which might have led to the current estimates being quite crude estimates of neurodevelopment in Haitian infants. Even so, we are confident that the differences estimated between the LBW and NBW are reliable.

LBW babies that survive any inpatient neonatal care in Haiti and live up to 24 months of age, will almost catch up to their NBW baby peers in terms of weight, length and fine motor skills. There does appear to be a delay in the LBW group in terms of gross motor, cognitive and communication skills development. Even though such delays are known to cause cognitive and behavioral problems in the future in other settings, the precise impact of these delays in the Haitian context would merit further research. Also, validating neurodevelopmental tools such as the Bayley scales for the Haitian pediatric population would be of added value, to better understand the clinical significance of delays observed. We will also further explore the current study data to identify specific maternal or hospital related interventions that impact positively on growth and neurodevelopment of LBW babies in order to better guide clinical management of LBW infants in low resource contexts.